Synthetic strategies towards challenging PPI drug targets

Moore, Thomas Oliver (2016) Synthetic strategies towards challenging PPI drug targets. Doctoral thesis (PhD), University of Sussex.

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Protein-protein interactions (PPIs) present a challenging target for the development of
inhibitors, due to the large size and lipophilicity of protein binding sites. Because of this,
work that is able to increase our understanding of how PPI inhibitors can be better
developed is of great value.
In unusual cases, approved drug compounds are able to exhibit excellent pharmacological
(PK) profiles despite having unfavourable physical properties. New methodology was
developed whereby the solubilising side chains found in one such compound, daclatasvir,
could be incorporated onto aryl-bromides using palladium-catalysed C-H activation. The
scope of the reaction was tested, and in 18 different examples the C-H activation was
found to be successful 11 times.1 This methodology has application in the potential
synthesis of cell-permeable PPI inhibitors.
Inhibiting the PALB2/BRCA2 PPI has the potential to produce synthetic lethality in
cancerous cells with damaged DNA repair mechanisms. Computational techniques were
used to design small-molecule and miniprotein mimetics of BRCA2, which could
potentially competitively inhibit PALB2/BRCA2. This resulted in the purchase of 10
miniprotein sequences ready for testing, one of which has been proven to have significant
helical secondary structure. The synthesis of small molecule α-helical mimetics of
BRCA2 has also been carried out, with one compound ready for biological testing and
the synthesis of two others close to completion.


1 T. O. Moore, M. Paradowski and S. E. Ward, Org. Biomol. Chem., 2016, 14,

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Library Cataloguing
Date Deposited: 19 Oct 2016 16:13
Last Modified: 13 Dec 2018 14:22

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